Antifungals

Antifungal Drugs
Sites of Drug Actions
• Fungal wall/cell membrane is vital to its survival and is different from mammalian cells
• Makes it a great target for drugs
• If cell wall loses rigidity, organism dies
• Ergosterol is the component of the cell membrane, not cholesterol -> drug target
Amphotericin B
• Broad spectrum, fungicidal macrolide polyene compound
• Macrocyclic, amphoteric molecule (similar to Daptomycin)
• Can act as both acid or base
• Soluble at both extremes pH and has lipid tail
• Mechanism
• Disrupts cell membrane by complexing with ergosterol
• Leakage of cell components
• Resistance
• Fungal replacement of ergosterol with something with less affinity
• Clinical usability is determined by formulation
• Due to problems with solubility, adverse reactions, and toxicity
• Lipid formulations decrease adverse infusion reactions (major toxicity)
• Premedicate with acetominophen/steroids
• Treat with meperidine if reaction occurs
Amphotericin B
• Four formulations
• C-AMB (conventional ampho B; bile acids)
• ABCD (ampho B complexed to cholesteryl synthase)
• L-AMB (Liposomal ampho-B) and ABLC (ampho B with lipids)
• Most used in US
• Choice of formulation major issue affecting toxicity and efficacy
• Nephrotoxicity is a major issue

• Based on dose given/serum levels
• Hypokalemia, hypomanganesemia, and renal tubular acidosis
• Non-anion gap metabolic acidosis (NAGMA)
• Anemia due to transient low EPO
• Reactions similar to Foscarnet
Flucytosine (5-
fluorocytosine)
• Fungi enzymatic deamination
converts to 5-FU (cancer
drug)
• Makes it active against those
cells only
• No mammalian interaction
• Metabolite of 5-FU blocks

Thymidylate Synthetase
action and fungal DNA
production is inhibited
• Only antifungal to act on DNA
rep.
Flucytosine
• Absorption, toxicity, clinical use
• Good GI absorption -> orally useful
• 80% excreted unchanged in urine
• Renal failure can lead to serious prolongation of T½
• Clearance is equal to creatinine clearance
• Toxicity due to conversion to 5-FU by gut bacteria
• Hair loss, bone marrow suppression, mucositis/enterocolitis
• Resistance happens when used as monotherapy for
cryptococcal and candidal infections
• Loss of permease
• Needed to enter fungal cell
• Decreased activity of uPRTase or cytosine deaminase
• Need to use in conjunction with ampho B b/c of
resistance
Azoles
• Imidazoles: Ketoconazole, miconazole, clotrimazole
• Triazoles: Fluconazole, voriconazole, itraconazole
• Mechanism - fungistatic
• Block fungal p450 from producing
ergosterol precursor
• Fungi p450s 100-1000x more
sensitive to azoles than mammalian
p450s
• Absorption and metabolism
• Oral, good penetrance, lower toxicity
compared to ampho B
• Good for systemic antifungal treatment
• Triazoles metabolized slower and less
cross-reactivity
• Given topical or systemically
• Topical gets to much higher
concentrations at site of infection and
may be fungicidal
Azoles
• Resistance
• Mutations that affect drug binding, but not natural substrate
binding
• Carries across all drugs in class
• Efflux Pumps
• Drug interactions are a major issue
• Interferes with p450 metabolism of other drugs and may reach
toxic levels if paired with a p450 inhibitor
• This class of drugs is commonly given and therefore presents a
problem
• Yeast infections, jock itch, athlete’s foot, fungal toenail infections, ringworm
• Systemic use is overused and creates greater interaction problems
• Toxicity of other drugs is mediated through inhibition of
mammalian p450
• Will appear as toxic overdose of drug that is normally metabolized by
mammalian p450
• Adverse effects are liver dysfunction and estrogenization due to
effects on the liver
Azoles
• Ketoconazole -> cross-reactivity to inhibit sterol synthesis in
mammalian cells allows it to be used as treatment for
Cushing’s Syndrome
• Itraconazole (Sporonox) -> ok for renal failure
• Major hepatotoxicity and death can occur
• Causes CHF in pts with LV dysfunction
• Nausea and vomiting in 10% of patients
• Fluconazole (Diflucan) -> major use if for candidal infections
• Dose adjustments need for renal failure and dialysis patients
• Teratogenic and rarely causes hepatic failure and death
• Voriconazole -> nonlinear metabolism
• Female on drug must be on contraceptive (most teratogenic: cat. D)
• QTc prolongation can cause arrhythmias and sudden death
• Visual and auditory hallucinations
• Retains activity against some resistant fungi: still used clinically
• Efinaconazole (Jublia) -> topical for onchomycosis (toenail)
Echinocandins -
•
Caspofungin
Prevent synthesis of glucans
• Chitin cross-linkage interupted
• Interferes with cell wall rigidity
• Inhibits glucan synthase
complex (GSC only on fungi)
• Absorption, Metabolism,
Toxicity
• IV only and cannot penetrate
CSF
• Circulate bound to protein
• Prevent renal clearance
• Hepatic failure has little effect on clearance
• Less toxic than ampho B -> used for non-CNS infection
• Caspofungin increases tacrolimus levels, is metabolized in liver,
and has no significant toxicity
Griseofulvin
• Super lipophilic and needs to be taken with fatty food in order to be
effective
• Mechanism
• Inhibits microtubule formation by binding alpha/beta tubulin in spindle and
microtubule-associated protein
• Has distinct binding sites on fungi MT
• Fungal morphology becomes multinucleated due to disruption of cell
cytoskeleton
• Deposits in precursors to keratin-producing cells almost exclusively
• Used in dermatophyte infections
• Promotes the growth of non-infected precursors over long period
• Adverse Reactions
• Safe in both kids and adults
• Most common rxn is headache (15%). Peripheral neuritis and altered mental
status can be seen
• Also watch for rash-like rxn: urticaria, erythematous multiforme, and
photosensitivity
• Cyt p450 inducing -> warfarin interactions
Terbinafine
• Systemically active allyamine that blocks squalene
epoxidase
• Inhibits ergosterol synthesis
• Good bioavailability (99% bound to protein); 40% first
metabolism
• Overcome this by increasing dosage
• Uses
• Dermatophyte infections b/c of localization (see griseofulvin)
• Contraindications
• Uremia, liver failure, and pregnancy
• Metabolism
• CYP3A4 (has drug interactions with others because of this)
• T½ is 12 hrs first, then >200hrs
• Topical only in same class: Naftifime, butenafime (Lotrimin
Ultra)
Topical Only – Nystatin and Tavaborole
• Complexes with ergosterol like ampho B, but is not
absorbed from mucosal surface
• Surface Candidal infections only
• Swish and swallow (esophageal), diaper rash, oral
• Not used in invasive infections
• Tavaborole
• Oxaborole class
• New drug used for
onchomycosis

Antifungals

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Antifungals

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Antifungal Drugs

Sites of Drug Actions

• Nephrotoxicity is a major issue

• Metabolite of 5-FU blocks

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